Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors
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Yoshimi Ohashi1,*, Mutsumi Okamura1,*, Ryohei Katayama2, Siyang Fang1, Saki Tsutsui1, Akinobu Akatsuka1, Mingde Shan3, Hyeong-Wook Choi3, Naoya Fujita2, Kentaro Yoshimatsu4, Isamu Shiina5, Takao Yamori1,6 and Shingo Dan1
1Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
2Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan
3Eisai AiM Institute, Eisai Inc., Andover, MA, USA
4Tsukuba Research Labs., Eisai Co., Ltd., Tokyo, Japan
5Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Tokyo, Japan
6Present address: Center for Product Evaluation, Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
*These authors contributed equally to this work
Shingo Dan, email: [email protected]
Keywords: Golgi apparatus; ADP ribosylation factor 1 (Arf1); non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); acquired resistance
Received: August 02, 2017 Accepted: November 17, 2017 Published: December 06, 2017
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) were demonstrated to provide survival benefit in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR; however, emergence of acquired resistance to EGFR-TKIs has been shown to cause poor outcome. To overcome the TKI resistance, drugs with different mode of action are required. We previously reported that M-COPA (2-methylcoprophilinamide), a Golgi disruptor, suppressed the growth of gastric cancers overexpressing receptor tyrosine kinases (RTKs) such as hepatocyte growth factor receptor (MET) via downregulating their cell surface expression. In this study, we examined the antitumor effect of M-COPA on NSCLC cells with TKI resistance. As a result, M-COPA effectively downregulated cell surface EGFR and its downstream signals, and finally exerted in vivo antitumor effect in NSCLC cells harboring secondary (T790M/del19) and tertiary (C797S/T790M/del19) mutated EGFR, which exhibit acquired resistance to first- and third generation EGFR-TKIs, respectively. M-COPA also downregulated MET expression potentially involved in the acquired resistance to EGFR-TKIs via bypassing the EGFR pathway blockade. These results provide the first evidence that targeting the Golgi apparatus might be a promising therapeutic strategy to overcome the vicious cycle of TKI resistance in EGFR-mutated NSCLC cells via downregulating cell surface RTK expression.
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